Process of making 3, 20-disemicarbazone of cortisone acetate



UnitedStates Patent Ofitice PROCESS OF MAKING 3,20-DISEMICARBAZONE FCORTISONE ACETATE Robert Joly, Montmorency, Gerard Nomine, Noisy-le-Sec, and Jean Jolly, Fontenay-sous-Bois, France, assignors to LesLaboratoires Francais de Chimiotherapie,

' France, a French body corporate No Drawing. Original application April13, 1955, Serial No. 501,174. Divided and this application April 11,1957, Serial N0. 652,097

Claims priority, application France July 29, 1954 1 Claim. (Cl.260397.45)

The present invention relates to a process of making the3,20-disemicarbazone of cortisone acetate.

application is a division of our co-pending application Serial No.501,174, filed April 13, 1955, and entitled: The 3,20-disemicarbazone ofCortisone Acetate and a Process of Making Same.

It is known to produce the acetate of hydrocortisone(11,9,170,21-trihydroXy-A -pregnene-3,20-dione) by reducing the3,20-disemicarbazone of free cortisone by CH20.00.CHa

NH.CO.NH2 I 2,849,463 Patented Aug; 26, 1958 CH20.0C.CHs

O l----on Q N: ILELCQNH: III

Direct formation of the 3,20-disemicarbazone of Formula I from the bromoketone of Formula 11 would be of considerable importance, because itwould permit elimination of three steps in the synthesis ofhydrocortisone.

The bromo ketone of tate were believed to yield exclusively themonos'emireaction conditions and in the presence of an excess of thereagent. This result is attributed to steric hindrance at theZO-carbonyl group in virtue of a neighboring ester function at position21. Preparation of said monosemicarbazone Was elfected in acetic acidsolution at a temperature of -75 C.

It is one object of the simple 3,20-disem1carbazone of cortisone acetatecorresponding Other objects of the present invention and advantageousfeatures thereof will become apparent as the description proceeds.

In principle, the process according to the present invention comprisesthe reaction of sone acetate. The reaction ence of disodium phosphateand care is taken that the reaction temperature does not substantiallyexceed 50 C. In view of the teachings of the prior art it is completelyunexpected and quite surprising that the disemicarbazone is formedthereby.

The following example serves to illustrate the present invention,without, however, limiting the same thereto.

EXAMPLE Preparation of the 3,20-disemicarbaz0ne of cortisone acetate ofFormula I by using cortisone acetate as starting material cc. of aceticacid containing 1.5% of water are heated to a temperature of 40-45 C.while passing a current of nitrogen gas therethrough. 16 g. of cortisoneacetate, 20 g. of semicarbazide hydrochloride, and 45 g.

is carried out in the pres- The reaction mixture is then poured into1500 cc. of lukewarm water. The resulting aqueous mixture is cooled in arefrigerator, the precipitated crystals are filtered off, washed, dried,and recrystallized from ethoxy ethanol. Thereby 16.4 g. of thedisemicarbazone .are .obtained. The yield amounts to 80% of thetheoretical yield. The pure disemicarbazone of cortisone acetatedecomposes, on heating, above 240 C.;rotatory power [u] =+198 *:3(concentration: 1% in pyridine; a 269 mu; e =32,400 (ethanol).

We claim:

In a process of preparing the 3,20-disemicarbazone of cortisone acetate,the steps comprising heating cortisone acetate at a temperature notsubstantially exceeding 50 10 C. in acetic acid containing about 1.5% ofwater in a nitrogen atmosphere with about 5 mols of semicarbazideReferences Cited in the file of this patent UNITED STATES PATENTS2,590,993 McGuckin et al. Apr. 1, 1952 OTHER REFERENCES Handbook ofChemistry, Lange, 8th edition, 1952, page 939.

